BSF-190555, BTS-79018, -Drug Synthesis Database

【结构式】

【药物名称】BSF-190555, BTS-79018

【化学名称】N-[7-Chloro-1,4-benzodioxan-2(S)-ylmethyl]-N-[1-(2-methoxyphenyl)piperidin-4-ylmethyl]amine

【CA登记号】170353-17-0 (undefined isomer), 170352-95-1 (undefined isomer; HCl salt)

【分子式】C₂₂H₂₇ClN₂O₃

【分子量】402.92509

【开发单位】Abbott (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Partial Agonists, Dopamine D2 Antagonists, Dopamine D3 Antagonists

合成路线1 合成路线2

合成路线1

Condensation of isonicotinamide (I) with 1-chloro-2,4-dinitrobenzene (II) gave quaternary pyridinium salt (III). This was further converted into pyridinium salt (V) by treatment with 2-methoxyaniline (IV) in MeOH. Catalytic transfer hydrogenation of the pyridine ring of (V) provided piperidine (VI). The amide function of (VI) was then reduced to amine (VII) using either borane-dimethyl sulfide complex or LiAlH4. Condensation of 4-chlorocatechol (VIII) with epichlorohydrin (IX) in aqueous KOH produced a mixture of regioisomeric benzodioxans (X) and (XI), from which the major 7-chloro isomer (X) was isolated by flash chromatography after treatment with tosyl chloride and pyridine yielding tosylate (XII). This compound was finally coupled with amine (VII) in the presence of K2CO3 and KI in boiling acetonitrile.

参考文献中间体

【1】 Kerrigan, F.; Heal, D.J.; Martin, K.F. (The Boots Company plc); Bicyclic aromatic cpds. as therapeutic agents. EP 0717739; JP 1997502431; US 5767116; WO 9507274 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	25191	isonicotinamide	1453-82-3	C₆H₆N₂O	详情	详情
(II)	10378	1-Chloro-2,4-dinitrobenzene	97-00-7	C₆H₃ClN₂O₄	详情	详情
(III)	25192	4-(aminocarbonyl)-1-(2,4-dinitrophenyl)pyridinium chloride	475-25-2	C₁₂H₉ClN₄O₅	详情	详情
(IV)	25193	2-methoxyphenylamine; 2-methoxyaniline	517-28-2	C₇H₉NO	详情	详情
(V)	25194	4-(aminocarbonyl)-1-(2-methoxyphenyl)pyridinium chloride		C₁₃H₁₃ClN₂O₂	详情	详情
(VI)	25195	1-(2-methoxyphenyl)-4-piperidinecarboxamide		C₁₃H₁₈N₂O₂	详情	详情
(VII)	25196	[1-(2-methoxyphenyl)-4-piperidinyl]methylamine; [1-(2-methoxyphenyl)-4-piperidinyl]methanamine		C₁₃H₂₀N₂O	详情	详情
(VIII)	25197	4-chloro-1,2-benzenediol	2138-22-9	C₆H₅ClO₂	详情	详情
(IX)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(X)	25199	(7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol		C₉H₉ClO₃	详情	详情
(XI)	25198	(6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol		C₉H₉ClO₃	详情	详情
(XII)	25200	(7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate		C₁₆H₁₅ClO₅S	详情	详情

合成路线2

The reaction of 5-chloro-2-hydroxybenzaldehyde (I) with the chiral glycidyl tosylate (II) by means of K2CO3 in DMF gives the condensation product (III), which is oxidized with m-chloroperbenzoic acid to formyl ester (IV). The cyclization of (IV) with sodium methoxide in methanol affords the hydroxymethyl benzodioxane (V), which is tosylated with tosyl chloride in pyridine to the tosylate (VI). Finally, this compound is condensed with 1-(2-methoxyphenyl)piperidin-4-ylmethylamine (VII) by means of K2CO3 in refluxing acetonitrile.

参考文献中间体

【1】 Birch, A.M.; Needham, P.L.; Kerrigan, F.; Gill, J.C.; Bradley, P.A.; N-substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D2 antagonists/5HT1A partial agonists with potential as atypical antipsychotic agents. J Med Chem 1999, 42, 17, 3342.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	26408	5-chlorosalicylaldehyde; 5-chloro-2-hydroxybenzaldehyde	635-93-8	C₇H₅ClO₂	详情	详情
(II)	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情
(III)	26409	5-chloro-2-[(2R)oxiranylmethoxy]benzaldehyde		C₁₀H₉ClO₃	详情	详情
(IV)	26410	5-chloro-2-[(2R)oxiranylmethoxy]phenyl formate		C₁₀H₉ClO₄	详情	详情
(V)	26411	[(2S)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol		C₉H₉ClO₃	详情	详情
(VI)	26412	[(2R)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate		C₁₆H₁₅ClO₅S	详情	详情
(VII)	25196	[1-(2-methoxyphenyl)-4-piperidinyl]methylamine; [1-(2-methoxyphenyl)-4-piperidinyl]methanamine		C₁₃H₂₀N₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)